Three-year Short-term Specific Immunotherapy (SIT): A Multi-centre, Double-blind Placebo-controlled Study with L-tyrosine adsorbed Pollen Allergoids

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1 Three-year Short-term Specific Immunotherapy (SIT): A Multi-centre, Double-blind Placebo-controlled Study with L-tyrosine adsorbed Pollen Allergoids Introduction KJ Drachenberg, U Feeser, and P Pfeiffer Bencard Allergie GmbH, Munich, Germany Since its introduction more than 80 years ago, specific immunotherapy (SIT) has gained more and more acceptance by allergists as an effective therapy in appropriately diagnosed patients. During the last 15 years in particular SIT has become recognised as the only causal treatment of IgE-mediated allergies other than avoidance measures (1,4). This trend is due to availability of better characterised and standardised allergen extracts for diagnosis and therapy and, in particular, to the improved understanding of the immunological background of allergic diseases. It is now thought that an imbalance of TH-2/TH-1 functionality of T-helper-cells in the immune system is the main reason for induction and maintenance of Type I (IgE-mediated) sensitisation (2,3). Over the years some progress has been made in achieving better tolerated and effective therapeutic allergen products compared to the original aqueous extracts, i.e. the development of adsorbates (e.g. aluminium hydroxide or L-tyrosine as carrier) and allergoids (chemically modified allergens). Allergy Therapeutics Ltd. (ATL), London (in Germany Bencard Allergie GmbH) have successfully used chemically modified tyrosine adsorbed pollen allergens (MATA grasses/rye, MATA trees) for more than 20 years. MATA products are L-tyrosine-adsorbed, glutaraldehyde-modified pollen extracts. The conformational protein structure is changed by the modification, so that binding of IgE is not possible or limited depending on the degree of modification. L- tyrosine is a natural amino acid and both a component of proteins and a biochemical precursor. In order to provide treatment to the high number of patients sensitised to birch, mugwort, plantain and grasses in combination, the preparation TA MIX has been available commercially in Germany as a named patient product since March TA MIX consists of combinations of birch, mugwort, plantain with MATA grass/rye allergoid extracts dispensed in formulations prescribed by physicians for patients with individual sensitisation patterns. Page 1 of 7

2 Rationale Phase I studies with birch, mugwort and plantain allergoid extracts showed no increased irritability in normal individuals, while the Phase II studies demonstrated a drastic reduction in skin reactivity to the trial substances in sensitised patients (5). In further studies on tolerability (Phase III), doses of 300 standardised units (SU), 800 SU and a maximum of 2000 SU of the birch, mugwort and plantain pollen allergoids were tested following subcutaneous injection into the lateral upper arm at weekly intervals (5). These studies demonstrated excellent tolerability at the above-mentioned dosages which was equivalent/comparable to that of MATA Tree and MATA Grass Pollens. All components of the birch, mugwort and plantain pollen allergoids and various formulations of it have been employed clinically and tested in safety studies. Study objective To confirm the safety and optimise the formulation of the TA MIX preparation, this clinical trial was designed to show superiority of birch, mugwort and plantain pollen allergoids and/or grass/rye pollen allergoids in five different combinations (TA MIX) after three preseasonal specific immunotherapies (SIT) over placebo with respect to the reduction of allergic symptoms. Study design The study was planned as a double-blind randomised (active:placebo = 2:1) multicentre, placebo-controlled comparative clinical trial with two parallel treatment groups for each allergoid combination during the first year of treatment. For the second treatment year, the investigator was given the option of continuing treatment with active without unblinding the first year. This resulted in 4 different groups from the second year onwards. The first two groups were blinded active/placebo all through, the third group was placeboblinded/activeopen/activeopen and the fourth group activeblinded/activeopen/activeopen. The trial was carried out in 7 clinical centres in Germany. In total, 106 adults (age over 18) were enrolled with seasonal allergic symptoms, a positive skin-prick test and positive RAST specific to their respective sensitisation. The total number of patients was divided into the following allergoid combinations: 23 (birch, 100%), 23 (birch + grass/rye, 50%/50%), 24 (birch + mugwort + grass/rye, 33%/33%/34%), 17 (mugwort + grass/rye, 50%/50%) and 19 (mugwort + plantain + grass/rye, 33%/33%/34%). Patients with contraindications to specific immunotherapy were excluded. Enrolled Patients received each year 6 injections with 3 increasing doses (300, 800, 2000 SU / 0.5 ml) and 3 maximum top dosages (2000, 2000, 2000 SU / 0.5 ml) of the respective allergoid combination in 1 to 4-weekly intervals (Fig. 1). Placebo patients received 4 % L-tyrosine. During the relevant pollen season of each treatment year allergic symptoms and rescue medication were scored in a standardised manner and documented in patient diaries. Page 2 of 7

3 Statistics As primary target variables efficacy was evaluated firstly by total symptom assessment jointly from both investigator and patient during the relevant three pollen seasons compared to the previous pollen season and secondly the symptom and medication score for the relevant three pollen seasons by evaluation of the patient diaries. The total symptom assessment was weighted and calculated using the following formulae. Diaries were considered evaluable providing they were kept during the local pollen season. At the request of the regulatory authorities two interim analyses were introduced at the end of the first and second pollen season, in addition to the final analysis planned in the original protocol. Adjustments to the analysis were made to accommodate three analyses, by adopting a type I risk of error of That is to say tests here are considered to show statistically significant differences between treatment groups when p<0.02. Confidence intervals were transformed to the confidence coefficient = As the primary graphical data inspection showed non-symmetric distributions and median values remarkably differed from related mean Page 3 of 7

4 values, a non-parametric approach was chosen using medians and confidence limits of the median as primary descriptive statistics and a suitable significance test (one sided Mann-Whitney Wilcoxon test). Due to the study design, efficacy was determined for comparison of active with two different placebo cohorts: - historical placebo group (a pool of all patients who received placebo treatment in the first treatment year) - ordinary placebo group (patients who received placebo treatment for 3 years) As a secondary parameter, efficacy was determined by comparison of serum IgG and IgE before and after treatment for either birch, mugwort, plantain, grasses and rye. Safety was evaluated by the incidence rates of local, systemic reaction and other adverse events. The treatment groups were compared with respect to demographic and anamnestic variables to detect baseline differences. 7 patients were not considered as intent-to-treat (ITT) population (e.g. no treatment, exclusion criteria). All other 99 patients met the inclusion criteria in accordance with the study protocol and were considered as ITT. Results Patient population Historical placebo compared with active treatment. The patient group consisted of 26 female and 42 male patients with a mean age of 30. Remarkable difference could not be observed with respect to sex, age, weight and height and anamnestic data, degree and allergen spectrum of sensitisation, duration of the disease, degree and distribution of symptoms. Before treatment, the placebo patients had a significantly reduced symptomatic medication consumption (p = , one sided Chi2-test) in comparison to activetreated patients. For the evaluation of the symptom and medication score in the patient diaries, the patient group consisted of 32 placebo and 27 active patients. Ordinary placebo compared with active treatment The patient group consisted of 12 female and 30 male patients. Remarkable differences could not be observed with respect to sex, age, weight and height and anamnestic data, degree and allergen spectrum of sensitisation, duration of the disease. Before treatment, the active patients had a significantly elevated incidence of lung symptoms (p = , one sided Chi2-Test) and a significantly elevated medication consumption (p = , one sided Chi2-Test) in comparison to placebo patients. For the evaluation of the symptom and medication score in the patient diaries, the patient group consisted of 10 placebo and 27 active patients. Page 4 of 7

5 Efficacy: total symptom improvement The improvements in or worsening of the symptoms assessed by the investigator and self-assessed by the patient during the pollen seasons were entered in the CRFs separately for each organ (eyes, nose and lung). The change was expressed as a percentage on a visual analogue scale. Percentages between 100% and 0% denote a deterioration, while those between 0% and +100% denote an improvement in the symptoms in the respective organ as compared to those experienced in the previous year: the higher the percentage, the greater the improvement and viceversa. The analysis of the combined organ-related symptoms (eye-nose-lung) showed a highly significant superiority of active versus the historical placebo treatment (p<0.001). The comparison of the combined organ-related symptoms for the ordinary placebo versus active treatment showed a significant result for nose (p=0.0166) and lung (p=0.0157) despite the low patient number in the ordinary placebo cohort (n=12). Efficacy: patient diary Data analysis of the patient diaries for the historical placebo versus active treatment (n=59) led to p < (Fig. 2) for the symptom score. The figure indicates a median difference between treatment groups of 74%. Data analysis of the patient diaries for the medication score (n=55) led to p < (Fig. 3). The same data analysis for the ordinary placebo versus active treatment (n=37) showed a significant result (p=0.0163) for the symptom score despite the low patient number in the placebo group (n=10). Page 5 of 7

6 Immunological parameters The data of all 99 patients were evaluable for the analysis of the immunological parameters. Preliminary results from graphical data inspection show a reduction in IgE for birch, grasses, rye and mugwort. Due to the small number of patients with an allergy to plantain (n=19) no tendency could be established. Safety Adverse events were evaluated after each treatment year. The results below feature the safety of the third treatment year only (n=106). The incidence and distribution of adverse events in the first two treatment years were similar. Local reactions (itching, swelling, pain at injection site) were documented in 4/13 placebo patients and in 44/93 active blinded/open patients (p < 0.001). In total, 8 local reactions were documented within the placebo group during 76 injections (11%), whereas 178 local reactions were reported for the open active group in 355 injections (50%) and 62 local reactions for the blinded active group in 189 injections (33%). Systemic reactions were documented in 1/13 placebo patients and in 8/93 active open/blinded patients (p=0.0011). Moderate to severe conjunctivitis was reported for 2 open active patients. In total, 1 systemic reaction was documented within the placebo group during 76 injections (1%) whereas 24 systemic reactions were reported for the open active group in 355 injections (7%) and 1 systemic reaction for the blinded Verum group in 189 injections (1%). The incidence of systemic reactions was significantly lower (p < 0.001) in the blinded active group when compared to the open active group. No serious reaction was reported. Page 6 of 7

7 Conclusion 6-shot specific immunotherapy with TA MIX (birch, mugwort and plantain pollen allergoids and/or grass/rye pollen allergoids in five different combinations) administered preseasonally over 3 years demonstrated highly significant and relevant clinical improvement in the active group compared to placebo. Treatment was well tolerated. References 1. Position Paper: Immunotherapy (1993) Allergy, 48, no.14, supplement. 2. Romagnani S. (1992) Human TH1 and TH2 Subsets: Regulation of Differentiation and Role in Protection and Immunopathology Int. Arch. Allergy Immunol., 98, Durham SR (1995) New insights into the mechanisms of immunotherapy Eur. Arch. Otorhinolaryngol., 252 (suppl.), Bousquet J, Lockey RF, Malling H-J. (1998) Allergen immunotherapy: therapeutic vaccines for allergic diseases. WHO Position Paper. Allergy, 53, Data on file (1992), SmithKline Beecham Pharma. Page 7 of 7